This improved recall also occurred when brain-damaged mice not treated with the HDAC inhibitor were placed in an enriching environment. According to Tsai, the mice are normally kept in a small cage with not much more than food and water. Moving them to a larger cage with lots of toys, a running wheel, and other mice to interact with allows them to be “much more active, physically and mentally,” she says. Mice in this stimulating environment exhibited much better freezing behavior, showing that they were able to recover their long-term memories.
Both the HDAC inhibitor and the enriching environment probably stimulate the growth of connections between neurons, which rewire the brain in such a way as to make long-term memories more accessible, Tsai says. “You don’t necessarily see an increased number of neurons,” she explains, “but you do see an increase in the formation of dendrites and synapses.” In the case of the HDAC inhibitors, it might be that changing the structure of the chromatin causes genes that affect this synaptic growth to be expressed more.
The results are “very impressive,” says Ya-Ping Tang, a neurobiologist at the University of Chicago. It shows how epigenetics–altered gene expression that is not linked to changes in the DNA itself–is involved in learning and memory, he says.
It’s not clear why initiating brain damage in the mice doesn’t destroy the long-term memories altogether. “Our study can’t speak to that,” Tsai says, “but it shows that even with this substantial neuronal loss, it’s not enough to get rid of memory.”
Tang says that it’s too early to say if drugs based on this mechanism could be developed to help restore memory loss in humans. Tsai and her group are now trying other HDAC inhibitors in mice to see which ones function best. “It will be very interesting to see if HDAC inhibitors will help in humans,” she says. “It really provides hope for people with neuronal loss and dementia that maybe something can be done.”